This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypercholesterolemia is a major contributor to heart attacks and other cardiovascular diseases. Recently, the orphan receptors, LXRa and FXR, were shown to play key roles in the control of cholesterol homeostasis. These receptors form heterodimers with RXR, the nuclear receptor for 9-cis retinoic acid. Their role in cholesterol control comes from their ability to regulate the expression of the cholesterol 7a-hydroxylase gene, the rate limiting enzyme of bile acid synthesis as well as other protein involved in cholesterol and bile acid elimination. These findings suggest that FXR and LXR are new targets for drugs that control cholesterol levels. To rationally design and test drugs that target these receptors, it will great help if we learn the precise details of how known ligands bind to the FXR and LXRa ligand binding domains. This proposal focuses on structural studies of the heterodimer of ligand binding domains (LBDs) of human FXR/RXR, LXRa/RXR and FXR with several ligands identified to date. We are attempting to obtain high resolution structural information that will provide us more information to understand details of the ligand binding pockets of FXR/RXR and LXR/RXR, how these different ligands are recognized and the conformational change upon the formation of ternary complex. These studies will provide a useful start point for future design of drug molecules that could target these receptors for the purpose of controlling cholesterol and bile acid levels in humans